Major trauma is accompanied by an endocrine response, mediated in part by the sympathetic system. Sympathetic adrenergic stimulation promotes survival in stressful situations by altering hemodynamics (pressor effect) and post-traumatic systemic metabolism (coordinating glucose supply to essential organs). Our investigations indicate an additional beneficial effect that promotes end organ tolerance to subsequent shock (ischemia-reperfusion, IR). this attenuation of subsequent injury is termed preconditioning and appears to be mediated via ae1 adrenergic receptors. Interestingly we have found that transient shock itself serves as preconditioning signal, but only if it precedes sustained shock (ischemia) by a few minutes. However sudden trauma may not permit the prerequisite delay between the preconditioning signal and ischemia. therefore the goal of this proposal is to delineate the preconditioning mechanisms conferring tolerance, so that a distal step in this endogenous cascade can be activated during or after sustained shock to improve survival. We have investigated this protective phenomenon using the model where preconditioning was first documented (rat heart). Recent reports of preconditioning in skeletal muscle and free-flaps suggest this protection is inducible in multiple organs. The heart is very vulnerable to IR injury which can be reproducibly quantified. The cardiac adrenergic receptors and signal transduction pathways have much in common with the pathways in other end-organs, but have the advantage of being biochemically, pharmacologically and functionally better characterized. Our evidence suggests that transient shock elicits local release of the sympathetic neurotransmitter, norepinephrine which preconditions by stimulating post-synaptic alpha1 adrenergic receptors. Norepinephrine induced preconditioning is not due to its pressor effects. Rather, our preliminary results indicate that preconditioning involves metabolic changes mediated by the adrenergic pathway which are persistent, even after inotropic and chronotropic effects have completely resolved. whereas ischemia-reperfusion impairs mitochondrial O2 uptake, preconditioning prevents this lesion and enhances ATP resynthesis. In lieu of norepinephrine release induced by transient shock, preconditioning may be achieved by brief infusion of exogenous norepinephrine. Stimulating the ae1 adrenergic pathway distally would allow preconditioning without the increased end-organ O2 demand or elevated vascular resistance induced by norepinephrine. Therefore, the aims of this proposal are to: 1. Characterize the preconditioning effect of transient shock (transient ischemia, TI) on recovery of end organ function (isolated heart) following a subsequent ischemia- reperfusion insult. 2. Investigate the role of the sympathetic neurotransmitter, norepinephrine (NE), in mediating preconditioning induced by transient ischemia. 3. Investigate the role of the adrenergic pathways in transducing preconditioning induced by NE. 4. Investigate the role of the ischemic metabolite, adenosine, in mediating preconditioning induced by TI or ae1 pathway. 5. Characterize the upregulation of energy metabolism as the basis of preconditioning.